Morus alba L. (Sangzhi) alkaloids reduce polycystic ovary syndrome by improving hypothalamic-pituitary-ovarian axis function

BACKGROUND: Polycystic ovary syndrome (PCOS) is a neuroendocrine-metabolic disorder with no approved drugs. Hypothalamic-pituitary-ovarian (HPO) axis dysfunction is core pathogenesis, and metabolic heterogeneity complicates treatment. Existing medications rarely ameliorate PCOS comprehensively. Sangzhi alkaloids (SZ-A), an extract from Morus alba L. twigs approved for type 2 diabetes in China, have not been systematically explored for PCOS. PURPOSE: To clarify the therapeutic effect and the mechanisms of SZ-A in PCOS. STUDY DESIGN: Animal studies, in vitro experiments and a placebo-controlled clinical trial. MATERIALS AND METHODS: In vivo: Obese/non-obese PCOS rats received oral SZ-A 67, 100, 150 mg/(kg·d) for 21 days (positive controls: Diane-35, metformin). In vitro: Granulosa cell apoptosis induced by dihydrotestosterone was treated with SZ-A 25, 50, 100, 200 μg/ml. CLINICAL: 6-month placebo-controlled trial (128 PCOS patients; oral SZ-A 300 mg/d, n = 88; placebo, n = 40). Multi-omics/Western blotting explored HPO pathways. RESULTS AND DISCUSSION: In rats, SZ-A (67 to 150 mg/(kg·d), 21 days) dose-dependently reduced androgens, regularized estrous cycles, and improved ovarian morphology. In vitro, SZ-A (25 to 200 μg/ml) protected granulosa cells from apoptosis. In patients, 6-month SZ-A (300 mg/d) lowered free androgen index and improved menstrual regularity versus placebo. Mechanistically, SZ-A inhibited hyperandrogenism-induced granulosa cell apoptosis and regulated GnRH secretion and downstream signaling pathways. CONCLUSION: SZ-A exerts therapeutic effects on PCOS by modulating HPO axis function through multiple pathways. TRIAL REGISTRATION: ChiCTR2200065097.